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Phosphoinositide 3-kinases (PI3K) are important drug targets for developing tumor treatments, due to their involment with various signaling pathways and cell functions such as cell growth, proliferation, apoptosis and intracellular trafficking and drug resistance. In the last few years, new applications for non-tumor related diseases are also slowly emerging.
THURSDAY, NOVEMBER 3
1:30 pm Chairperson’s Remarks
1:40 Inhibiting the PI3K Pathway in Cancer: Scalpels, Knives or Axes?
Joseph R. Garlich, Ph.D., CSO, Semafore Pharmaceuticals
Evolving cancer biology is revealing new information about the PI3K pathway that has tremendous implications for how best to block the pathway to maximize anticancer effects. For example different PI3K isoforms have been reported to be critical players in different types of cancer and non-PI3K pathways are found to become up-regulated which thwarts efficacy. The latest trends in this rapidly changing field will be discussed along with a case study of the clinical stage multi-kinase inhibitor SF1126 designed to maximally block the PI3K pathway.
2:10 Targeting PI3K Delta: A New Paradigm for the Treatment of B-Cell Malignancies that Involves the Tumor Cell and its Microenvironment
Brian Lannutti, Ph.D.,Senior Scientist II, Oncology Research, Gilead Sciences
2:40 VPS34, A Class III PI3K: A Potential Novel Drug Target for Cancer Therapy
Wen Jin Wu, Principal Investigator, Division of Monoclonal Antibodies (DMA), Office of Biotechnology Products (OBP), FDA
We find that Src, which plays an important role in the regulation of cancer development and progression, directly phosphorylates Vacuolar protein sorting 34 VPS34, and that this phosphorylation resulted in the activation of VPS34 to mediate cellular transformation. We also find that the levels of VPS34 expression and tyrosine phosphorylation are correlated with the tumorigenic activity of human breast cancer cells, suggesting that VPS34 may be involved in cancer development and a potential novel drug target for breast cancer therapy.
3:10 Networking Refreshment Break in the Exhibit Hall with Poster Viewing
3:45 Discovery and Optimization of Selective ATP-Competitive mTOR Inhibitors
Emily Peterson, Ph.D., Scientist, Medicinal Chemistry, Amgen, Cambridge
A novel class of triazine-benzimidazole mTOR inhibitors was discovered that demonstrated > 100X selectivity over structurally related kinases PI3Kα, β, γ, and δ. Modification of this scaffold guided by structure-based drug design resulted in a secondary scaffold, which demonstrated improved selectivity and pharmacokinetic properties. A lead molecule from this series was efficacious in a U87 xenograft tumor model.
4:15 The Identification of Clinical Candidate, AZD8055: A Potent, Selective Small Molecule Dual Inhibitor of mTORC1 and mTORC2
Kurt Pike, Ph.D., Team Leader, Medicinal Chemistry, AstraZeneca, UK
Two alternative approaches to identify selective inhibitors of the mTOR kinase domain resulted in the identification of two distinct lead series. The identification and optimization of these series will be described, culminating in the discovery of AZD8055, a potent and selective inhibitor of both mTORC1 and mTORC2. AZD8055 demonstrates dose-dependant tumor growth inhibition in xenograft studies and is currently undergoing clinical evaluation as a potential cancer therapy.
4:45 PWT33597, A Novel PI3 Kinase alpha/mTOR Inhibitor: Translation to the Clinic
David J. Matthews, Ph.D., Vice President, Drug Discovery and Exploratory Development, Pathway Therapeutics, Inc.
Dysregulation of both PI3 kinase and mTOR signaling is prevalent in cancer, prompting the discovery and development of drugs targeting these critical pathways. PWT33597 is a novel, highly selective inhibitor of PI3 kinase alpha and mTOR. The pre-clinical profile of PWT33597 will be discussed, together with data supporting the translation of these results into clinical studies.
5:15 Palomid 529 (P529), an Allosteric Dual TORC1/TORC2 Inhibitor of the PI3K/Akt/mTOR Pathway – Results from the Clinic
David Sherris, Ph.D., CEO, CSO, Paloma Pharmaceuticals
Aberrant up-regulation of the PI3K/Akt/mTOR pathway is involved in a variety of human diseases including retinal diseases of neovasculature and cancer. Normalization of the pathway could then be expected to potentially ameliorate such diseases. However as the pathway is complex with multiple branch points, cross-talk between other pathways and internal feedback inhibition, it is not a particularly simple task to adequately control the pathway to effect activity of disease states. We have shown in a variety of in vitro and in vivo animal models that disruption of both the TORC1 and TORC2 complexes by the allosteric inhibitor P529 could both normalize activation of the pathway and inhibit disease in a variety of animal models. We believe that allosteric inhibition of the TORC complexes via their dissociation as opposed to catalytic inhibition of mTOR is key to this activity. Here we will show in in vitro and in vivo studies activity of P529 as well as interim results in our Phase I human trial of P529 in age-related macular degeneration.
5:45 End of Day
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